Branched-chain amino acids as a novel biomarker and treatment for Alzheimer's disease

项目摘要 阿尔茨海默病（AD）是一种破坏性的、不可逆的神经退行性疾病，影响超过500万人 仅在美国的个人。不幸的是，目前还没有治愈或有效的治疗AD， 准确评估个体易感性和预测未来AD发展的工具增加了 另一层复杂性。今天，医生依靠几种生物标志物来诊断AD患者， 但是目前的评估方法存在严重的局限性，例如使用放射性同位素， 腰椎穿刺风险高，费用高。显然，更可靠，侵入性更小，对患者更友好 因此，非常需要能够预测和/或诊断AD发作的生物标志物。初步数据显示， 支链氨基酸（BCAA）及其代谢产物在AD患者中升高， AD小鼠的转基因小鼠模型与健康对照相比。根据这些发现，BCAA是 在我们的预测模型中被鉴定为AD的显著复合预测因子（图1A和1B）。1和2）。而且有 大量研究表明，过量的支链氨基酸可诱导神经氧化应激和细胞凋亡，触发胰岛素 大脑中的阻力，并抵消这些神经递质的平衡。有趣的是，所有这些都代表了 AD的病理生理学特征，表明BCAAs在AD发病机制中的潜在致病作用。 AD.我们的试验数据表明，在成熟的海马神经元中补充支链氨基酸可以诱导 AD中常见的神经元功能障碍（图3），使BCAA成为一个有吸引力的干预靶点， 治疗AD。在拟议的研究实验将利用转基因，分子，综合生理学， 行为方法检查1）AD样症状发作前后的BCAA代谢， 在一个完善的转基因小鼠模型（APP/PS1）中的脑病理学，以确定血浆BCAA和 它们的代谢物可以作为AD的预测和/或诊断生物标志物;以及2）膳食BCAA是否 操纵改变了体内AD的进展。这些发现将确定用于预测的新生物标志物， AD的检测，并提供新的见解BCAA及其代谢的发展的影响， AD.

Project Summary Alzheimer's disease (AD) is a devastating, irreversible neurodegenerative disorder that affects over 5 million individuals in the US alone. Unfortunately, currently there is no cure or effective treatment for AD, and the lack of tools to accurately assess an individual's susceptibility and predict one's future development of AD adds another layer of complexity. Today, doctors are relying on several biomarkers to diagnose individuals with AD, but there are serious limitations with current assessment methods such as the use of radioactive isotopes, high-risk lumbar puncture, and the high cost. Clearly, more reliable, less-invasive, and patient-friendly biomarkers that can predict and/or diagnose the onset of AD is highly desired. Our preliminary data show that branched-chain amino acids (BCAAs) and their metabolites are elevated in humans with AD as well as a transgenic mouse model of AD mice compared to healthy controls. In line with these findings, BCAAs are identified as a significant composite predictor of AD in our predictive model (Figs. 1 and 2). Furthermore, a number of studies suggest that excess BCAAs can induce neural oxidative stress and apoptosis, trigger insulin resistance in the brain, and offset the balance of those neurotransmitters. Interestingly, all of these represent the pathophysiological hallmarks of AD, indicating a potential causative role of BCAAs in the pathogenesis of AD. Our pilot data show that BCAA supplementation in mature hippocampal neurons induces features of neuronal dysfunctions commonly observed in AD (Fig. 3), making BCAAs an attractive interventional target to treat AD. Experiments in the proposed study will utilize transgenic, molecular, integrative physiology, and behavioral approaches to examine 1) BCAA metabolism before and after the onset of AD-like symptoms and brain pathologies in a well-established transgenic mouse model (APP/PS1) to determine if plasma BCAAs and their metabolites can serve as a predictive and/or diagnostic biomarker for AD; and 2) whether dietary BCAA manipulation alters the progression of AD in vivo. The findings will identify novel biomarkers for prediction and detection of AD and provide new insights into the impact of BCAAs and their metabolism in the development of AD.